1. Field of the Invention
This invention relates to a device for effectively removing pyrogens from aqueous solutions.
2. Description of the Prior Art
Pyrogens, the protein organic matter or complex polysaccharide of a fever producing nature frequently found in sterile water, are produced by a certain group of bacteria which enter and develop in water during distillation and subsequent storage. During sterilization they are killed leaving their bodies and products of decomposition in the solution. They are said to be responsible for the majority of reactions following intravenous injections. The entity primarily responsible for pyrogenic reactions in mammals is the lipopolysaccharide (LPS) from Gram-negative bacteria. A comprehensive discussion of lipopolysaccharides and the pyrogenic response can be found in Good, C. M., et al., "I. The Biochemistry of Pyrogens", Bulletin of the Patenteral Drug Association, vol. 31, no. 3 (1977).
Prior to the present invention, water for injection was prepared using relatively expensive distillation and reverse osmosis equipment which was not wholly effective in the removal of pyrogens. It has been found that pyrogens are quantitively removed by a pinhole-free assymetric ultrafiltration membrane. An ultrification membrane, often referred to as an anisotropic or "skinned" membrane, consists of a thin polymeric film or skin supported on or bonded to a highly porous substrate. The substrate contributes strength and durability to the filter, but the thin skin is the actual molecular filtration membrane. The skin layer is densely structured to retain molecules, but because it is very thin, typically less than 2 microns, the resistance to flow caused by the dense structure is minimized. Since the skin is backed by a very open, porous substrate layer, flow rates through the filter are high.
Skinned membranes retain most molecules above a nominal limit as well as some fraction of smaller molecules. They do not retain all molecules larger than an absolute cut-off size. Although several factors affect the ability of a molecule to pass through a skinned membrane, the efficiency of retention for a particular solute is primarily determined by the size and shape of the solute molecules. However, because it is not possible to detect discrete pores in skinned membranes which can be measured accurately and it is difficult to measure the apparent diameter of most large molecules in solution, meaningful size limits cannot be assigned to skinned membranes. Since molecular weight is an approximate guide to molecular size, skinned membranes can be conveniently characterized by their percent retention of selected solutes of globular proteins having accurately known molecular weights. From these data, each membrane can be assigned a nominal molecular weight limit (NMWL), i.e. a molecular weight at and above which most species are efficiently retained by that membrane.
The removal of pyrogens required for water for injection is 5 orders of magnitude or 99.999 percent. For such reduction, only 10.sup.-5 part of the flow should be allowed to pass through the pinholes of an otherwise pyrogen excluding ultrafiltration membrane. Ultrafiltration membranes containing pinholes and other inherent defects remove about 3 orders of magnitude of pyrogens from aqueous solutions. It is extremely difficult to make large areas of an ultrafiltration membrane pinhole-free, and even if it were possible to make one completely pinhole-free, the cost would be prohibitive.